U.S. patent application number 10/706708 was filed with the patent office on 2004-05-20 for composition and method for the treatment of onychomycosis in animals.
Invention is credited to Tarbet, Bryon J..
Application Number | 20040096519 10/706708 |
Document ID | / |
Family ID | 30002557 |
Filed Date | 2004-05-20 |
United States Patent
Application |
20040096519 |
Kind Code |
A1 |
Tarbet, Bryon J. |
May 20, 2004 |
Composition and method for the treatment of onychomycosis in
animals
Abstract
This invention relates to a composition and method for the
treatment of white line disease, including ailments such as
onychomycosis, sporotichosis, hoof rot, jungle rot, pseudallecheria
boydii, scopulariopsis or athletes foot. The composition of the
present invention is useful for the treatment of fungal infections
such as onychomycosis in warm blooded animals such as humans and
horses. The method of the present invention is directed to the
application of a therapeutic amount of the present composition.
Inventors: |
Tarbet, Bryon J.; (Highland,
UT) |
Correspondence
Address: |
Kenneth Tarbet
1652 Seattle Slew Way
Oceanside
CA
92057
US
|
Family ID: |
30002557 |
Appl. No.: |
10/706708 |
Filed: |
November 11, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10706708 |
Nov 11, 2003 |
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09545486 |
Apr 10, 2000 |
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6680073 |
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60128604 |
Apr 8, 1999 |
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Current U.S.
Class: |
424/638 ;
424/616; 514/355; 514/423 |
Current CPC
Class: |
A61K 31/30 20130101;
A61K 33/40 20130101 |
Class at
Publication: |
424/638 ;
424/616; 514/355; 514/423 |
International
Class: |
A61K 033/40; A61K
033/34 |
Claims
1. A composition for the treatment of an animal afflicted with
onycomychosis, the composition comprising: 2Where R.sup.1 is
hydrogen, alkyl, hetero, heteroalkyl, aryl or heteroaryl; R.sup.3
is hydroxy, alkyl, hetero, heteroalkyl, aryl or heteroaryl; R.sup.2
is hetero; each r.sup.7 is independently hydrogen, alkyl, hetero,
heteroalkyl, aryl or heteroaryl and; a copper composition; a
peroxide; a polyhydroxy aromatic compound; a transition metal
coordination composition; all admixed in a hydrophyllic carrier
composition.
2. The composition according to claim 1 wherein R.sup.2 is
oxygen.
3. The composition according to claim 2 wherein the copper
composition is a copper complex.
4. The composition according to claim 3 wherein the copper complex
is a diamine polymer-copper complex.
5. The composition according to claim 1 wherein the coordination
composition is a Co chelate or complex.
6. The composition according to claim 1 wherein the coordination
composition is a Zn chelate or complex.
7. The composition according to claim 1 wherein the coordination
composition is a Fe chelate or complex.
8. The composition according to claim 1 wherein the polyhydoxy
aromatic compound is a 1,2,4,5-tetra hydroxy benzene.
9. The composition according to claim 1 wherein the peroxide is an
organic peroxide.
10. The composition according to claim 1 wherein the peroxide is an
inorganic peroxide.
11. The composition according to claim 1 wherein the peroxide is
hydrogen peroxide.
12. The composition according to claim 1 wherein the hydrophyllic
carrier is between about 50% to about 99% by weight water.
13. The composition according to claim 1 wherein the hydrophyllic
carrier is between about 1% to about 50% a compound according to
formula II 3wherein R.sup.4 is a heteroatom, R.sup.5 is a
heteroalkyl or heteroatom-H and R.sup.6 is --CH.sub.3,alkylaryl,
aryl or heteroaryl and n and x are independently between 1 and
20.
14. The composition according to claim 1 wherein the hydrophyllic
carrier is between about 0.1% to about 30% by weight alcohol.
15. A pharmaceutical composition for the topical treatment of
onychomychosis comprising a composition according to claim 1 and a
pharmaceutically acceptable carrier.
16. A method for the treatment of white line disease comprising:
applying to an afflicted area the whiteline treating composition
according to claim 1.
17. the method according to claim 16 further comprising cleaning of
the afflicted area prior to application of the whiteline treating
composition.
18. The method according to claim 17 wherein cleaning of the
afflicted area consists essentially of debrideing.
19. A method of preventing whiteline disease comprising the steps
of: a) applying to a site in need of treatment a suitable amount of
a whiteline treating composition according to claim 1; b) applying
to the site a barrier composition.
20. The method according to claim 19 wherein the barrier
composition is a barrier to water.
21. The method according to claim 19 wherein the barrier
composition is a barrier to oxygen.
22. The method according to claim 19 further comprising cleaning
the site prior to application of the whiteline treating
composition.
23. The method according to claim 22 wherein the cleaning of the
site comprises the steps of: i) applying a cleaning composition to
the afflicted area; ii) causing at least a partial removal of the
afflicted tissue.
24. The method according to claim 23 wherein steps I and ii are
repeated.
25. The method according to claim 23 wherein the cleaning
composition is a surfactant.
26. The method according to claim 23 wherein the cleaning
composition contains an enzymatic composition.
Description
RELATED APPLICATIONS
[0001] This application is a divisional of co-pending application
Ser. No. 09/545,486 which claims the priority filing date of the
Provisional application serial No. 60/128,604, Apr. 8, 1999.
FIELD OF THE INVENTION
[0002] This invention relates to a composition and method for the
prevention and treatment of fungal infections such as
sporotrichosis, onychomycosis infections, hoof rot, jungle rot,
pseudallecheria boydii, scopulariopsis, athletes foot, canker sole
and fungal infections generally. The composition of the present
invention is useful for the treatment of fungal infections in
warm-blooded animals such as humans and horses. The method of the
present invention is directed to the application of a therapeutic
amount of the present composition.
BACKGROUND OF THE INVENTION
[0003] Conditions such as onychomycosis and other fungal infections
pose serious problems in dermatology. It has been estimated that
the prevalence of onychomycosis in the general population is in the
range of 2-13% and increases to about 15-20% in the 40-60 year old
age group. Onychomycosis is a condition recognized by discoloration
beneath toe nails and finger nails along with pain when pressure is
placed near or at the site of discoloration. The condition usually
affects more than one nail. Various fungi, classified as white
superficial fungi, cause the condition. Frequently the condition is
treated by the combination of nail avulsion and application of a
pharmaceutical agent. Presently available topical antifungal
formulations for treating fungal infections have been met with
limited success. This is primarily due to the limited ability of
such compounds to penetrate into the nail plate, which is
hyperkeratotic. The treatment of the condition is further
problematic in geriatric patients where therapeutic options are
often limited due to possible drug interactions, systemic side
effects of treatment, and contraindications secondary to other
medical ailments.
[0004] The treatment of fungal infections of the nail and hoof
generally falls into three categories: systemic administration of
antifungals; surgical removal of all or part of the nail or hoof
followed by topical treatment of the exposed tissue; or topical
application of conventional creams, lotions, gels or solutions,
frequently including the use of bandages to keep these dosage forms
in place on the nail or hoof. All of these approaches have major
drawbacks.
[0005] Long term systemic (oral) administration of an antifungal
agent for the treatment of onychomycosis is often required to
produce a therapeutic effect in the nail bed. For example, oral
treatment with the antifungal compound ketoconozole typically
requires administration of 200 to 400 mg/day for 6 months before
any significant therapeutic benefit is realized. Such long term,
high dose systemic therapy can have significant adverse effects.
For example, ketoconozole has been reported to have liver toxicity
effects and reduces testosterone levels in blood due to adverse
effects on the testes. Patient compliance is a problem with such
long term therapies especially those which involve serious adverse
effects. Moreover, this type of long term oral therapy is
inconvenient in the treatment of a horse or other ruminants
afflicted with fungal infections of the hoof.
[0006] Accordingly, the risks associated with parenteral treatments
generate significant disincentive against their use and
considerable patient non-complience. However, these and other
related hindrances to treatment can be potentially avoided through
the appropriate use of a therapeutically effective of a composition
according to the present invention. Moreover, the present invention
provides a method for the administration of an effective amount of
the present invention comprising the application of the composition
to an area in need of treatment and maintaining the composition in
contact therewith for an effective period of time.
[0007] Surgical removal of all or part of the nail followed by
topical treatment also has severe drawbacks. The pain and
discomfort associated with the surgery and the undesirable cosmetic
appearance of the nail or nail bed represent significant problems,
particularly for female patients or those more sensitive to
physical appearance. Generally, this type of treatment is not
realistic for ruminants such as horses.
[0008] Topical therapy has significant problems too. Topical dosage
forms such as creams, lotions, gels etc., can not keep the drug in
intimate contact with the infected area for therapeutically
effective periods of time. Bandages have been used to hold drug
reservoirs in place in an attempt to enhance absorption of the
pharmaceutical agent. However the bandages are thick, awkward,
troublesome and generally lead to poor patient compliance.
[0009] Hydrophilic and hydrophobic film forming topical antifungal
solutions have also been developed. These dosage forms provide
improved contact between the drug and the nail, but the films are
not occlusive. Topical formulations for fungal infection treatment
have largely tried to deliver the drug to the target site (an
infected nail bed) by diffusion across or through the nail.
[0010] Nail is more like hair than stratum corneum with respect to
chemical composition and permeability. Nitrogen is the major
component of the nail attesting the to the nail's proteinaceous
nature. The total lipid content of mature nail is 0.1-1.0%, while
the stratum corneum lipid is about 10% w/w. The nail is 100-200
times thicker than the stratum corneum and has a very high affinity
and capacity for binding and retaining antifungal drugs.
Consequently little if any drug penetrates through the nail to
reach the target site. Because of these reasons topical therapy for
fungal infections have generally been ineffective.
[0011] Compounds known as penetration or permeation enhancers are
well known in the art to produce an increase in the permeability of
skin or other body membranes to a pharmacologically active agent.
The increased permeability allows an increase in the rate at which
the drug permeates through the skin and enters the blood stream.
Penetration enhancers have been successful in overcoming the
impermeability of pharmaceutical agents through the skin. However,
the thin stratum corneum layer of the skin, which is about 10 to 15
cells thick and is formed naturally by cells migrating toward the
skin surface from the basal layer, has been easier to penetrate
than nails. Moreover, known penetration enhancers have not proven
to be useful in facilitating drug migration through the nail
tissue.
[0012] Antimicrobial compositions for controlling bacterial and
fungal infections comprising a metal chelate of 8-hydroxyquinoline
and an alkyl benzene sulfonic acid have been shown to be
efficacious due to the increased ability of the oleophilic group to
penetrate the lipoid layers of micro-cells. The compounds however,
do not effectively increase the ability to carry the
pharmaceutically active antifungal through the cornified layer or
stratum corneum of the skin. U.S. Pat. No. 4,602,011, West et al.,
Jul. 22, 1986; U.S. Pat. No. 4,766,113, West et al., Aug. 23,
1988.
[0013] The composition of the present invention is directed a
method and composition for treating onychomychosis, and related
infections, in animals. Because onychomychosis is an infection
afflicting all animals with a nail or hoof, this composition is
useful in the treatment of any animal with a nail or hoof.
[0014] Onychomychosis is a fungal infection of the nail or hoof
bed. Because the infection is under the nail or hoof it is very
dificult to treat. Traditional methods of treatment involve
complete nail removal in humans. Not infrequently the chosen
treatment regime involves nail removal combined with topical
treatment of the now exposed infected tissue. However, the removal
of an infected hoof requires complete imobilization of the animal,
an often impossible task. This treatment regime is therefore
unreasonable for the treatment of hoofed animals, such as
horses.
[0015] Topical treatments have also been employed. However, because
the nail is largely impervious to the transfer of drugs, little of
the applied drug reaches the infected tissue. This problem is more
pronounced in hoofed animals where the nail is many time thicker
than the nail of a human.
[0016] However if white line disease is allowed to grow unchecked,
it can result in the crippling of the animal. The unbchecked growth
of the fungus in humans often inflicts substantial pain.
[0017] The inventor has solved the problem of treating a human
afflicted with onychomychosis, without surgery. Moreover, the
present invention solves this long felt need through the
formulation of a composition which has unique properties relative
to migration into the infected site.
[0018] It would therefore be useful to provide a composition for
the treatment of onychomychosis and related infections in
animals.
[0019] It would further be useful to provide a mehtod for the
administration of the present composition for the treatment of
onychomychosis in animals.
DESCRIPTION OF THE INVENTION
[0020] These and other objects of the invention are accomplished
through a method of treatment of the infected nail or hoof and a
composition to be applied to the infected nail/hoof comprising a
composition consisting essentially of a compound according to
firmula I: 1
[0021] Where R.sup.1 is hydrogen;
[0022] R.sup.3 is hydroxy;
[0023] R.sup.2 is hetero;
[0024] each R.sup.7 is independently hydrogen, alkyl, hetero,
heteroalkyl, aryl or heteroaryl and;
[0025] a copper composition;
[0026] a peroxide;
[0027] a polyhydroxy aromatic compound;
[0028] a transition metal coordination complex;
[0029] all dissolved in water, wherein the composition contains
greater than 100 mg copper composition.
[0030] The composition according to the present invention is
directed to the treatment of fungal infections in animals
comprising:
[0031] at least one element such as an element selected from
columns Ia through column VIa of the periodic chart of the
elements, preferably an element selected from columns IIa through
column IVa and most preferably a transition metal selected from the
group comprising column IIIb to column IIb and where the element is
in ionic form. The element in ionic form means an element in a
state other than its elemental state, such Cu.sup.+2 or Cu.sup.+1
or Ag.sup.+1. The element in ionic form can be from any source, but
usually from the oxide, carbonate, hydroxide or other salt of the
element such as CuSO.sub.4, CuO, CuOH.sub.2 or
Ag.sub.2SO.sub.4.
[0032] at least one chelating or complexing agent selected from the
group consisting of a carboxylic acid, hydroxyaryl carboxylic acid,
thioaryl carboxylic acid, a heteroaryl carboxylic acid, a
heteroatom substituted aryl carboxylic acid, a hydroxy heteroaryl
carboxylic acid, crown ether, hetero crown ether, tributyl tin
oxide, thiol, diamine, triamine, glycols thioglycols and
aminoglycols.
[0033] In the composition according to this invention the metal,
the chelating or complexing agent and optionally a peroxide are
combined in a polar solvent at a suitable temperature and for a
suitable period of time to allow the solvation of the added
ingredients.
[0034] Although not wanting to be bound by any theory or presented
hypothesis, a brief analysis of the chemistry involved may be
useful in understanding the invention.
[0035] It is known that transition metals are cytotoxic if
introduced into a cell. For example, 12 is bactericidal when
applied topically, and the use of metallic copper as an antibiotic
is also known. It is therefore believed that the introduction of a
toxic metal into the cellular system of the fungal organism will
cause it to die. The present invention seems to cause, or at least
assists in the introduction of a metal into the cellular system of
the fungus. This is accomplished through the formation of a
chelate, complex or salt between a metal and an organic agent such
as salicylic acid or thiosalicylic acid and administering this
composition to the infected site. The formation of any one specific
chelate or complex structure is not essential for the proper
functioning of the composition nevertheless, a complex of
undetermined structure is likely formed in solution. In this
regard, it is desirable that the amount of the complexing agent be
in greater amounts than the metal in the composition, e.g. that the
complexing agent and the metal be in a ratio of greater than 1:1,
complexing agent:metal.
EXAMPLES
Example 1
[0036] The treatment solution was prepared by adding about 100-300
grams of salicylic acid to 4 Liters of warm water. This was
followed by 10-100 g NaOH and 1-60 grams of boric acid. The
solution was mixed and filtered to remove traces of undissolved
material. Then about 1-100 grams of copper sulfate where added and
the solution became a light green. Finally, the solution was
diluted to 20 L with water.
Example 2
[0037] To 1 liter of water is added 20 grams of thiosalicylic acid
and 0.5 grams copper sulfate. The solution is stirred sufficiently
to allow proper mixing. The solution changes from blue to amber,
indicating that an association with the copper and the complexing
agent has formed.
Example 3
[0038] The treatment solution was prepared by adding about 230
grams of salicylic acid to 4 Liters of warm water. This was
followed by 45 g NaOH and 25 grams of boric acid. The solution was
mixed and filtered to remove traces of undissolved material. Then
10 grams of copper sulfate where added and the solution became a
light green. The solution was allowed to cool and 1-100 mL of
hydrogen peroxide was added. Finally, the solution was diluted to
20 L with water.
Example 4
[0039] The treatment solution was prepared by adding about 230
grams of salicylic acid to 4 Liters of warm water. This was
followed by 45 g NaOH and 25 grams of boric acid. The solution was
mixed and filtered to remove traces of undissolved material. Then
50 grams of copper sulfate where added and the solution became a
light green. The solution was allowed to cool. Finally, the
solution was diluted to 20 L with water.
[0040] Salts of any metal may be used but water soluble metal salts
are preferred and water soluble salts of Ag, Cu, Ni and Co are most
preferred.
[0041] An organic moiety complexing agent such as an aryl
carboxylic acid, a hydroxyaryl carboxylic acid and a thioaryl
carboxylic acid are preferred and salicylic acid and thiosalicylic
acid are most preferred.
[0042] The inclusion of a peroxide, although optional, may be
included from the group comprising: organic and inorganic peroxides
such as hydrogen peroxide, benzoyl peroxide and acetyl
peroxide.
[0043] The above fungal infection treating composition is applied
in any manner that places the composition is contact with the
infected tissue. One method of application involves the use of a
syringe with out the needle. A syringe of suitable size is loaded
with the composition and sprayed or squirted in the space between
the hoof of the infected animal and the attach tissue. Substantial
amounts of black, decayed tissue and rotting matter may be
discharged after the first washing. A second application is
recommended to ensure the delivery of adequate amounts of the
fungal treating composition to the infected tissue.
[0044] The infected area may also be treated through the use of
cloth soaked in the fungal treating composition of the present
invention. For example, a cloth soaked in the composition may be
inserted into the space between the hoof and the attached tissue so
that the soaked cloth is in intimate contact with the infected
tissue, thereby placing the fungal treating composition in contact
with the infected tissue.
[0045] In general the infected tissue may be treated in any method
or manner that causes the infected tissue to be contacted with the
fungal treating composition of this invention.
* * * * *